Synaptic Plasticity and Addiction 2007

REVIEWS Synaptic plasticity and addiction Julie A. Kauer* and Robert C. Malenka‡ Abstract | Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plasticity mechanisms in key brain circuits, most importantly in the mesolimbic dopamine system, which is central to reward processing in the brain. Reversing or preventing these drug-induced synaptic modifications may prove beneficial in the treatment of one of society’s most intractable health problems. Long-term potentiation More than a century ago, Ramon y Cajal speculated that Addiction is not triggered instantaneously upon (LTP). Activity-dependent information storage in the brain results from alterations exposure to drugs of abuse. It involves multiple, com- strengthening of synaptic in synaptic connections between neurons1. The discov- plex neural adaptations that develop with different transmission that lasts at least ery in 1973 of long-term potentiation (LTP) of glutamate time courses ranging from hours to days to months one hour. synapses in the hippocampus2 launched an exciting (BOX 1). Work to date suggests an essential role for Long-term depression exploration into the molecular basis and behavioural synaptic plasticity in the VTA in the early behavioural (LTD). Activity-dependent correlates of synaptic plasticity. Partly because LTP was responses following initial drug exposures, as well as in weakening of synaptic first described at synapses in the hippocampus, a brain triggering long-term adaptations in regions innervated transmission that lasts at least 9 one hour. region necessary for declarative memory formation, by dopamine (DA) neurons of the VTA . By contrast, there was an early assumption that synaptic plasticity downstream synaptic changes in the NAc and other represents a cellular building block used exclusively for brain regions, are likely to represent the formation of learning and memory. However, it has since become powerful and persistent links between the reinforcing clear that LTP and its counterpart, long-term depression aspects of the drug experience and the multiple cues (LTD), are basic properties of most excitatory syn- (both internal and external) associated with that exp- apses throughout the CNS, and are used for multiple erience5–10. Here we review emerging evidence that brain functions in addition to learning and memory3. addictive drugs elicit or modify synaptic plasticity in For example, LTP and LTD appear to be essential in many of the key brain regions involved in addiction, the stabilization and elimination of synapses during the and that these synaptic modifications have important developmental fine-tuning of neural circuits in many behavioural consequences. A major motivation for areas of primary sensory cortex4. this research is the assumption that addictions to the It therefore may not be surprising that evidence accu- different classes of abused substances share important mulated over the last decade demonstrates that drugs of underlying brain mechanisms. Identifying these mecha- abuse can co-opt synaptic plasticity mechanisms in brain nisms will advance our ability to treat and prevent these circuits involved in reinforcement and reward process- often devastating disorders, as well as other related *Department of Molecular Pharmacology, Physiology ing. Indeed, an influential hypothesis is that addiction behaviours, such as gambling. and Biotechnology, represents a pathological, yet powerful, form of learning Of course, the brain adaptations that underlie addic- Brown University, and memory5–10. Although the brain circuitry underlying tion are complex and involve drug-induced changes Providence, Rhode Island addiction is complex, it is unequivocal that the mesolim- in essentially every parameter that has been studied 02912, USA. ‡Nancy Pritzker Laboratory, bic dopamine system, consisting of the ventral tegmental including gene transcription, membrane excitability and Department of Psychiatry area (VTA) and nucleus accumbens (NAc), as well as neuronal morphology. Moreover, because of advances and Behavioural Sciences, associated limbic structures (FIG. 1), are critical substrates in our understanding, and the societal importance, of Stanford University School for the neural adaptations that underlie addiction. It is the neurobiology of addiction, this topic has been the of Medicine, Stanford, also clear that the interactions between addictive drugs subject of numerous reviews in both the basic science California 94304, USA Correspondence to R.C.M. and synaptic plasticity in different brain regions will con- and clinical literatures. Thus, we will intentionally limit e-mail: [email protected] tribute to specific aspects of addiction, such as craving, our discussion primarily to those studies that most doi:10.1038/nrn2234 withdrawal and, perhaps most importantly, relapse. directly demonstrate drug-induced modulation of 844 | NOVEMBER 2007 | VOLUME 8 www.nature.com/reviews/neuro © 2007 Nature Publishing Group REVIEWS Conditioned place synaptic plasticity mechanisms and try to construct a repeated exposure. Given the critical role that NMDAR- preference coherent picture from an often confusing and, as yet, dependent synaptic plasticity is thought to have in nor- A behavioural task during incomplete literature. mal learning and memory13, these findings immediately which a subject learns to suggested that processes akin to associative learning are associate the drug experience Addiction and learning with a specific physical essential in the early development of addiction. 25–27 environment. A subject will Synaptic plasticity is required for neuroadaptations that Abundant additional evidence supports the choose to spend more time in result from a wide range of environmental stimuli. It was notion that excitatory synaptic function within meso- an environment in which it therefore attractive to hypothesize that drugs of abuse limbic dopamine circuits is crucial for the behavioural previously had a ‘rewarding’ cause long-term changes on behaviour by altering syn- responses to drugs of abuse. Furthermore, human experience and less time in an environment in which it had aptic function and plasticity in relevant brain circuits. imaging studies in addicted subjects demonstrate the an aversive experience. Moreover, data from diverse behavioural experiments powerful cognitive and emotional effects of cues that with drugs of abuse has implicated specific signalling were previously associated with the drug experience28. molecules already identified as key players in LTP and Preventing relapse is the major clinical problem in the LTD at other synapses10. Indeed, accumulating evi- treatment of addiction, suggesting the need to under- dence links various behavioural models of key features stand the cellular nature of the powerful ‘memories’ of addiction with synaptic plasticity in brain areas that caused by prior drug experiences. Thus, experimental process reinforcement and reward. work in animal models, as well as clinical studies, pro- Studies demonstrating that blocking !-methyl-"- vides compelling support for the importance of learning aspartate receptors (NMDARs) could short-circuit the and memory mechanisms in addiction. development of drug-induced behavioural adaptations in certain addiction models were among the first clues LTP and LTD mechanisms that addictive drugs might access the same processes that A ubiquitous property of all synapses is their ability are used to store learned information. For example, to undergo activity-dependent changes in synaptic NMDAR blockade, known to prevent many forms of strength, that is, synaptic plasticity. Much of the LTP and LTD in other brain regions3, also prevents mechanistic work on long-term synaptic plasticity in conditioned place preference, behavioural sensitization the mammalian brain over the last few decades has and self-administration of drugs of abuse14–21 (BOX 2). focused on the forms of LTP and LTD observed at excita- Furthermore, NMDAR blockade specifically within the tory synapses, although it is now clear that inhibitory VTA (but not the NAc) effectively prevents both behav- synapses can exhibit LTP and LTD as well. Synaptic ioural sensitization and conditioned place preference, plasticity can be studied most effectively using electro- supporting the idea that NMDAR-dependent processes physiological methods in brain slices that are viable for in the VTA might have a pivotal role in the development several hours, and therefore, the cellular mechanisms of addiction15–17. Importantly, NMDAR blockade does underlying the first few hours of LTP and LTD are the not prevent the acute locomotor response to psycho- best understood. Before discussing the interactions stimulant drugs, only the sensitization that occurs with between drugs of abuse and long-term synaptic plasticity, it is useful to review our mechanistic understanding of the most common forms of LTP and LTD (FIG. 2). Only by understanding these core synaptic mechanisms PFC can we hope to understand how drugs of abuse usurp Hippocampus or modify them. NMDAR-dependent LTP. NMDAR-dependent LTP, Striatum first observed in the hippocampus, has been intensively LDTg examined for over three decades and remains the best understood form of long-lasting synaptic plasticity

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